Potential therapeutic targets for the treatment of opioid abuse and pain

Although μ-opioid peptide (MOP) receptor agonists are effective analgesics available in clinical settings, their serious adverse effects put limits on their use. The marked increase in abuse and misuse of prescription opioids for pain relief and opioid overdose mortality in the past decade has seriously impacted society. Therefore, safe analgesics that produce potent analgesic effects without causing MOP receptor-related adverse effects are needed. This review highlights the potential therapeutic targets for the treatment of opioid abuse and pain based on available evidence generated through preclinical studies and clinical trials. To ameliorate the abuse-related effects of opioids, orexin-1 receptor antagonists and mixed nociceptin/MOP partial agonists have shown promising results in translational aspects of animal models. There are several promising non-opioid targets for selectively inhibiting pain-related responses, including nerve growth factor inhibitors, voltage-gated sodium channel inhibitors, and cannabinoid- and nociceptin-related ligands. We have also discussed several emerging and novel targets. The current medications for opioid abuse are opioid receptor-based ligands. Although neurobiological studies in rodents have discovered several non-opioid targets, there is a translational gap between rodents and primates. Given that the neuroanatomical aspects underlying opioid abuse and pain are different between rodents and primates, it is pivotal to investigate the functional profiles of these non-opioid compounds compared to those of clinically used drugs in non-human primate models before initiating clinical trials. More pharmacological studies of the functional efficacy, selectivity, and tolerability of these newly discovered compounds in non-human primates will accelerate the development of effective medications for opioid abuse and pain.